SUMMARY ? OVERALL A 27% increase in US suicides in the past 15 years demands a paradigm shift in prevention driven by research into causes of suicidal behavior. The Conte Center?s first 4 years of funding identified related brain changes in suicide and nonfatal suicidal behavior, indicating common causal factors and potential prevention by detecting future suicide decedents. Key findings include thinner prefrontal cortex and smaller dentate gyrus, partly due to neuronal loss. We found potential causal abnormalities in HPA axis and inflammasome indices and deficiencies in trophic systems including the serotonin system (more 5-HT1A autoreceptors) and low BDNF. These findings link genetics, childhood adversity, epigenetics, mood regulation and cognition to PET and fMRI abnormalities, stress responses and suicidal behavior. The current proposal seeks to study the neural circuitry and molecular detail of abnormal stress responses in suicide and nonfatal suicidal behavior, emphasizing potential etiological and pathogenic roles of the inflammasome, HPA axis and BDNF. Project 1 (Underwood /Boldrini) uses postmortem brain tissue from suicides with major depressive disorder (MDD) to examine childhood adversity (psychological autopsy), neuroinflammation and process/synaptic mass in prefrontal cortex, anterior cingulate cortex and hippocampus, and existing data on genomics (HPA, trophic/apoptotoic, GABA, Glu, 5-HT, BDNF), neuron and glial number, growth and apoptotic factors, HPA axis and the serotonin system. Project 2 (Champagne/Hen) applies a maternal separation mouse model to examine effects on homologous genomics, brain biology and depression, anxiety and aggressive behaviors in a mouse model of over-expressing 5-HT1A autoreceptors (geneXenviron). Project 3 (Mann) uses PET to quantify a depression/suicide/aggression/oxidative load-related neurotransmitter index (MAOA), a neuroinflammation marker (PBR28), & a synaptic marker (UCB-J) and Project 4 (Ochsner) uses fMRI to study mood regulation and memory in MDD suicide attempters, MDD nonattempters and healthy volunteers. Project 5 (Stanley) will use ecological momentary assessment and TSST biological stress responses (HPA, adrenergic and inflammatory) to study emotional and biological stress responses with respect to impulsive or planned suicidal behavior and reported childhood adversity. Project 6 (Ogden) will use high dimensional brain imaging, genomic and inflammasome data to develop statistical methods to measure suicidal risk. Findings are compared across projects in exploratory aims to test a model where childhood adversity leads to greater inflammation, impaired serotonin and BDNF trophic effects and long-lasting impaired stress responses related to altered brain morphology and function underlying risk of suicide.!